Chlamydomonas reinhardtii is a unicellular green alga whose lineage diverged from land plants over 1 billion years ago. It is a model system for studying chloroplast-based photosynthesis, as well as the structure, assembly, and function of eukaryotic flagella (cilia), which were inherited from the common ancestor of plants and animals, but lost in land plants. We sequenced the~120-megabase nuclear genome of Chlamydomonas and performed comparative phylogenomic analyses, identifying genes encoding uncharacterized proteins that are likely associated with the function and biogenesis of chloroplasts or eukaryotic flagella. Analyses of the Chlamydomonas genome advance our understanding of the ancestral eukaryotic cell, reveal previously unknown genes associated with photosynthetic and flagellar functions, and establish links between ciliopathy and the composition and function of flagella.

In the genetic code, UGA serves as a stop signal and a selenocysteine codon, but no computational methods for identifying its coding function are available. Consequently, most selenoprotein genes are misannotated. We identified selenoprotein genes in sequenced mammalian genomes by methods that rely on identification of selenocysteine insertion RNA structures, the coding potential of UGA codons, and the presence of cysteine-containing homologs. The human selenoproteome consists of 25 selenoproteins.

Selenium is an essential micronutrient with important functions in human health and relevance to several pathophysiological conditions. The biological effects of selenium are largely mediated by selenium-containing proteins (selenoproteins) that are present in all three domains of life. Although selenoproteins represent diverse molecular pathways and biological functions, all these proteins contain at least one selenocysteine (Sec), a seleniumcontaining amino acid, and most serve oxidoreductase functions. Sec is cotranslationally inserted into nascent polypeptide chains in response to the UGA codon, whose normal function is to terminate translation. To decode UGA as Sec, organisms evolved the Sec insertion machinery that allows incorporation of this amino acid at specific UGA codons in a process requiring a cis-acting Sec insertion sequence (SECIS) element. Although the basic mechanisms of Sec synthesis and insertion into proteins in both prokaryotes and eukaryotes have been studied in great detail, the identity and functions of many selenoproteins remain largely unknown. In the last decade, there has been significant progress in characterizing selenoproteins and selenoproteomes and understanding their physiological functions. We discuss current knowledge about how these unique proteins perform their functions at the molecular level and highlight new insights into the roles that selenoproteins play in human health.

Formate dehydrogenase H from Escherichia coli contains selenocysteine (SeCys), molybdenum, two molybdopterin guanine dinucleotide (MGD) cofactors, and an Fe 4 S 4 cluster at the active site and catalyzes the two-electron oxidation of formate to carbon dioxide. The crystal structures of the oxidized [Mo(VI), Fe 4 S 4(ox) ] form of formate dehydrogenase H (with and without bound inhibitor) and the reduced [Mo(IV), Fe 4 S 4(red) ] form have been determined, revealing a four-domain αβ structure with the molybdenum directly coordinated to selenium and both MGD cofactors. These structures suggest a reaction mechanism that directly involves SeCys 140 and His 141 in proton abstraction and the molybdenum, molybdopterin, Lys 44 , and the Fe 4 S 4 cluster in electron transfer.

The naked mole rat (NMR, Heterocephalus glaber) is a strictly subterranean, extraordinarily long-lived eusocial mammal1. Although the size of a mouse, its maximum lifespan exceeds 30 years and makes this animal the longest living rodent. NMRs show negligible senescence, no age-related increase in mortality, and high fecundity until death2. In addition to delayed aging, NMRs are resistant to both spontaneous cancer and experimentally induced tumorigenesis3,4. NMRs pose a challenge to the theories that link aging, cancer and redox homeostasis. Although characterized by significant oxidative stress5, the NMR proteome does not show age-related susceptibility to oxidative damage nor increased ubiquitination6. NMRs naturally reside in large colonies with a single breeding female, the “queen,” who suppresses the sexual maturity of her subordinates11. NMRs also live in full darkness, at low oxygen and high carbon dioxide concentrations7, and are unable to sustain thermogenesis8 nor feel certain types of pain9,10. Here we report sequencing and analysis of the NMR genome, which revealed unique genome features and molecular adaptations consistent with cancer resistance, poikilothermy, hairlessness, altered visual function, circadian rhythms and taste sensing, and insensitivity to low oxygen. This information provides insights into NMR’s exceptional longevity and capabilities to live in hostile conditions, in the dark and at low oxygen. The extreme traits of NMR, together with the reported genome and transcriptome information, offer unprecedented opportunities for understanding aging and advancing many other areas of biological and biomedical research.

Summary DNA methylation levels of certain CpG sites are thought to reflect the pace of human aging. Here, we developed a robust predictor of mouse biological age based on 90 CpG sites derived from partial blood DNA methylation profiles. The resulting clock correctly determines the age of mouse cohorts, detects the longevity effects of calorie restriction and gene knockouts, and reports rejuvenation of fibroblast-derived iPSCs. The data show that mammalian DNA methylomes are characterized by CpG sites that may represent the organism’s biological age. They are scattered across the genome, are distinct in human and mouse, and their methylation gradually changes with age. The clock derived from these sites represents a biomarker of aging and can be used to determine the biological age of organisms and evaluate interventions that alter the rate of aging.

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Summary Dietary restriction (DR) without malnutrition encompasses numerous regimens with overlapping benefits including longevity and stress resistance, but unifying nutritional and molecular mechanisms remain elusive. In a mouse model of DR-mediated stress resistance, we found that sulfur amino acid (SAA) restriction increased expression of the transsulfuration pathway (TSP) enzyme cystathionine γ-lyase (CGL), resulting in increased hydrogen sulfide (H2S) production and protection from hepatic ischemia reperfusion injury. SAA supplementation, mTORC1 activation, or chemical/genetic CGL inhibition reduced H2S production and blocked DR-mediated stress resistance. In vitro, the mitochondrial protein SQR was required for H2S-mediated protection during nutrient/oxygen deprivation. Finally, TSP-dependent H2S production was observed in yeast, worm, fruit fly and rodent models of DR-mediated longevity. Together, these data are consistent with evolutionary conservation of TSP-mediated H2S as a novel mediator of DR benefits with broad implications for clinical translation.